Process for the manufacture of 11beta-acyloxy steroids



United States Patent 2,781,369 t PROCESS FOR' MANUFACTURE OF llfi-AC OXYSTEROIDS Eugene P. Oliveto, Bloomfield, and Emanuel B. Hershberg, WestOrange, N. J., assignors to Scherlng Corporation, Bloomfield, N. J., acorporation of New Jersey No Drawing. Application October 22, 1952,

' Serial No. 316,324

8 Claims. (Cl. Z60397.45)

The present invention relates to the manufacture of ll-acyloxyderivatives of 11 fl-hydroxy steroids which have no other substituent inthe C-ring, and to the acylated products so obtained.

More particularly, the present invention relates to improved procedureswhereby 1lfi-hydroxy-perhydrocyclopentanophenanthrene compounds havingno other substituent in the C-ring, can be converted to the correspond-'ing llfl-acyloxy compounds.

The esterification of the llB-hydroxyl group of steroid compounds havingno other substituent in the C-ring, is desirable for protective purposesin the synthesis of various compounds having important physiologicalactivity, but efforts to acylate such 11B-hydroxyl group have heretoforebeen unsuccessful. Under the usual conditions of acetylation, such as bythe use of acetic anhydride and pyridine, the IIB-hydroxyl group eitherfails to esterify, or, when a reaction does occur, it results indehydration, forming a A -double bond. In all examples described in theliterature, aoetylation of an 11 B-hydroxyl of steroid compounds hasnecessitated the presence of a 3,9-epoxide, a 12-ketone, or some otheractivating neighboring group which must ultimately be eliminated.

We have found a new and simple method for the preparation of the newll-esters of ll'fl-hydroxy steroids having no other substituent in theC-ring. Our process consists in treating such 11 fl-hydroxy steroidswith an acetyl-v ating agent and with a strong acid catalyst but underotherwise mild conditions. For example, by the use of acetic anhydrideor isopropenyl acetate in the presence of p-toluene sulfonic acid atroom temperature, the 113- hydroxysteroids are converted intoIIB-acetoxy compounds. These acetylating conditions not only avoiddehydration at the C-ll hydroxyl, but also provide high yields of thedesired llfi-acetoxy steroid. This result was entirely unexpected inview of the failure of prior acylating processes to yield the lip-estersof the specified type of steroids, even under intensive acylationreaction conditions.

Our invention is not limited to acetylation, for with the proper choiceof acylating agent, such as propionic, butyric and other anhydrides,other preferably lower aliphatic acyl radicals may be introduced. Also,other strong acid catalysts may be used, such as trichloracetic, benzenesulfonic, sulfuric and perchloric acids. The reaction is a general oneand may be applied to any steroid with an llfl-hydroxyl groupunactivated by a neighboring substituent. For example, etiocholanes andandrostanes having the following structures can be easily prepared fromthe corresponding llfi-hydroxy compounds:

"ice

wherem R1 is a member of the group comprising 0;

OH no 10: y y

and

alkox y H CHsRt wherein R1 is as above defined; R2 is a memtter of thegroup comprising H, OH and acyloxy, and )2, X are a member of the groupcomprising H, H and a double bomiii Other hydroxyl groups which may beattached to the steroid nucleus will be acylated in the course ofi'ourpaocess. However, as will be shown below, all acylilxy'groups with theexception of the llfi-gro'up can be easily removed by alkalinehydrolysis. Our invention, by time utilizing the resistance of thellB-acyloxy group to hydrolysis, ac-

cordingly provides a novel method for the synthesis of physiologicallyactive llfi-acyloxy compounds: related to the adrenal and otherhormones, or of intermediates for use in the manufacture of suchhormones.

The following equations depict the synthesis of A-pregnen-l1,B,17a,21-tiiol-3,20-dione ll-acetate (compound F Il-acetate) ggrsnseo onus:

Meghan-311,11 5,17a-tril-20-0ne (I) is acetylated with, for example,acetic anhydride and acetic acid in the presence of p-toluene sulfonicacid to yield the triacetate II. Saponification with either hot sodiumcarbonate solution or aqueous sodium hydroxide removes th r-3 fi l d 17acetates to yield pregnan-3a,1lB,l7 -triol 2 Qone ll-ace; tate (III).Bromination of (3-21, followed by the usual methods of acetogtylation,yields the pregnantriolon e tate" V. Oxidation of the 3-hydroxyl Vto'giv trioldione diacetate VI can be performed with a var ety ofagents, such as N-bromacletat riide, N-bromsuccin'i'mide, potassiumchromate and 'ehr'oniic acid. Bromination at Gal with bromine and aceticacid why the method described in the co-pending application of Eugene P.Oliveta et al., Serial No. 287,612, for Process for the Bromination ofSteroids, filed May 13, 1952, followed by dehydrobromination in knownmanner yields the 11,21-diacetate VIII. Hydrolysis with either acid oralkali easily removes the (3-21 ester group, yielding compound Fll-acetate (IX).

Alternatively, the 21-bromide IV need not necessarily be converted tothe ZI-acetate. Eor example, the reaction of IV with sodium propionateo'rsodium benzoate yields the 2l-propionate and benzoate respectively,which in turn can be carried through the previous set of reactions. glso, hydrolysis of IV with sodium hydrorgide will give h ZI'hY XY c mp ud, wh ch can be car ied h h lt fijla nds ii t s qt Se uence. the re y;droxyl C -521, thereby yielding 'e pouna F l 1;ace fate withoutrst goingthrough the 2 l ester x A i o ou Pro u e c b u ed for e P 2? 4 n =ss lehesli fli s illi kets? 'Bi q idafii he .l -hwne ts III with bus o h he lidiz l l .a silio th re r oh a i sd nr nsnd oldi fis mpnoasst t In oduon of t e A1 doub e bon is accomplished by brominatiqn and,dehydrobromination in the usual manner to yield MI.

VIII

CHzOH The described invention has a number of important advantages overother processes." The 'llB-hydrox yl can now be protected in chemicalreactions which were heretofore either very difiicult or impossible toperform on 1lfl hydroxy steroids. For example, bromination at (3-21 inthe presence of an llfi-hydroiryl group resultsin a very small yield ofthe desired llrbrbli'lide because of the facile oxidation o'f tliellhydrtixyl group by the brominating miirture In addition, ox'idation'ofother hydroiylgr'oups' such as that at" C 3 in the presence of a C l'l'hydroiryl group heretoiore was best carried out by means of an Oppenauer reaction. However, thisproce dure is tedious and theyields remediocre. 'By protecting the llfi-hydroxyl groupwith an ester group,oxidation of the other hydroxyl groups can now be carried ou ql iokly,convl i fl an i h eld by me ns f qthef'wmnion and more eflicientoxidizing agents. In addition, all ofthe ti s hsnn n s Ql Ffl iih nlfi-hy o l group can now be converted to'th e"11} 3 -acetates orhomologous esters. These compounds, while qualitatively retaining h e lh s s sgi sl equ t e fis ns c l tes of absorptio 'nd thus generate acorre I E i f s P ss o e o ani m id r f lowin exa l s e be t in e tio iin greater detail but are presented only by way o'f'illu strat'io n, P9?a .s ins ssi n l sil s psi f th y fi EXAMPLPI Rregnarz-3 t,11 8,1 Za-triI-ZQ-Om: ,triacetate To a solution of 4.0 g. of pregnan-Ia'x,-11/3,17a-triol-20- one in ml. of acetic acid 511660 ml. of aceticanhydride is added 2.0 g. of p-toluene sulfonic acid. After standingovernight at 25 the solution is poured into water and the resultingsolid collected by filtration, washed with water and dried; Wt. 5.16 g,M. P. 18-74-94? Recrystallization from acetone-hexane yields 4.5 g. ofpregnan-B J1B,l7 t-trio1 2Q-one triacetateQMI P. 2 09- 210", [a] +54.3(chloroform). (The infrared spectrum shows no hydroxyl ,peak, andintegration of the acetate carbonyl frequencies gives a value inagreement with that expected for three acetate groups).

EXAMPLE II Pregnan-3a,11B,1 706-1 ril-20-0ne 1 1 acetate A solution of7.3 g. of pregnan-3a,115,17a-triQl-20-0ne triacetate in 585 ml. of C. P.methanol is added to 58 ml. of l N aqueous sodium hydroxide and themixture refluxed one and one-half hours. The excess alkali isneutralized by the addition of 4.5 ml. of acetic acid, and the methanolremoved by distillation under reduced pressure. The aqueous mixture isextracted with methylene chloride, and the organic phase Washed withwater, dried and evaporated. Crystallization from ether yields 4.8 g. ofpregnan-3a,11,8,17u-triol-20-0ne ll-acetate, M. P. 1l0ll1 with foaming,[a] +35.6 (chloroform). (The infra-red spectrum indicated that only oneacetate group remained; since there was no evidence of interactionbetween the acetate and a ketone carbonyl, the remaining acetate must beC-ll.)

Reacetylation with acetic acid, acetic anhydride and 'p-toluene sulfonicacid, yields the original triacetate, indicating that no dehydration orrearrangement had occurred during the hydrolysis.

The saponification can also be performed with a hot sodium carbonatesolution, or with aqueous sodium hydroxide at room temperature.

EXAMPLE III Pregnan-3u,11fl,1 711,21 -tetr0l-20-0ne 1 1 ,21 -diacetate Asolution of 3.0 g. of pregnan-3a,11,8,17a-triol-20-one ll-acetate in 30ml. of C. P. chloroform is brominated at 27 by the dropwise addition of1.22 g. of bromine in l5 ml. of C. P. chloroform. After removal of thesolvent under reduced pressure, 50 ml. of acetone and 6 g. of potassiumacetate are added, and the mixture refluxed for 5 hours. The acetone isremoved by distillation under reduced pressure, water added, and themixture extracted with methylene chloride. The organic extracts arewashed with water, dried and evaporated, giving 3.39 g. crudepregnan-3a,llfl,l7a,2l-tetrol-20-one 11,21-diacetate, M. P. l63l72.Recrystallization from acetonehexane yields 2.0 g., M. P. 175176, [a]+78.6 (chloroform).

EXAMPLE IV Pregnant-115,1 7u,21-triol-3,20-di0ne 11,21-diacetate Asolution of pregnan-3a,11B,17a,21-tetrol-20-one 11,- 2l-diacetate in 20ml. of acetone and 4 ml. of water is cooled in an ice bath, and 0.46 g.of N-brornoacetamide is then added. After standing overnight at 5, thesolution is poured into water containing 2 g. of sodium sulfite. Themixture is extracted with methylene chloride, and the extract washedwith water, dried and evaporated. Crystallization from aqueous methanolyields 0.33 g. of pregnan-l1B,17a,21-triol-3,20-dione 11,21-diacetate,M. P. 180-482", [a] +8l.O (chloroform).

EXAMPLE V M-pregnen-IlflJ 70,21-tri0l-3,20-di0ne-1I-acetate A solutionof 2.0 g. of pregnan-1lB,17a,21-triol-3,20-

dione 11,2l-diacetate in 10 ml. of methylene chloride,.

previously saturated with hydrogen bromide, and 10 m1. of t-butanol iscooled to 0. At this temperature, a solution of 760 mg. of bromine in 10ml. of methylene chloride and 10 ml. of t-butanol is added over a periodof ten minutes.

The solution is allowed to warm up to room temperature in order todischarge the residual bromine, and then concentrated under reducedpressure until solids appear. Water is then added and the crude4-bromopregnan- 1lfl,l7u,21-triol-3,20-dione ll,2l-diacetate removed byfiltration and dried. Pure 4-bromide is obtained by crystallization fromaqueous acetone.

A solution of 0.42 g. of semicarbazide hydrochloride and 0.3 g. ofsodium acetate in 3.5 ml. of .water and 15 ml. of acetic acid is quicklyadded to a suspension of 1.58 g. of the 4-bromide in 60 ml. of aceticacid while stirring and maintaining a gentle stream of carbon dioxide.After 15 minutes, 3.6 ml. of 1 N sodium acetate in acetic acid is addedand the stirring continued for 10 minutes longer. The gas stream isdiscontinued, and the solution refluxed for 10 minutes. After cooling,water is added and the mixture extracted with methylene chloride. Theorganic layer is washed with water, dried and evaporated. Thecrystallization of the residue from acetone-hexane yields A-pregnen-llfi, 17oz, 21-trio1-3,20-dione ll,2l-diacetate (compound Fll,21-diacetate).

EXAMPLE VI A -pregnen-1 1,9,1 70:,21-triol-3,20-di0ne-ll-acetateHydrolysis of the 115,21-diacetate by refluxing 1 hour with aqueousmethanolic sodium bicarbonate gave M-pregnen-l18,l7a,2l-triol-3,20-dione ll-acetate. (Compound F ll-acetate.)

EXAMPLE VII Pregnan-I 1fl,I7a-diol-3,20-dione 1 1 -acetate M-pregnen-I1,8,1 7a-diol-3,20-di0ne I I -acetate As described in the previousexamples, the pregnandioldione acetate from Example VII is brominated at04 by means of bromine in methylene chloride and t-butanol, and hydrogenbromide is eliminated by the semicarbazide procedure to yield A-pregnen-1lfi,l7ot-diol-3,20-dione llacetate.

EXAMPLE IX A -pregnen-1 1 3,1 7a-d1'0l-3,20-di0ne 1 1,1 7-diacetate Thepregnendioldione acetate of Example VIII is acetylated with aceticanhydride and p-toluene sulfonic acid at room temperature to giveM-pregnen-l1,6,17a-diol-3,20- dione 11,17-diacetate.

EXAMPLE X Pregnan-3a,1 1 3,1 7a,20p-tetrol tetra'acetate One gram ofpregnan-3a,1lfi,17u,20;3-tetro1 is dissolved in 50 ml. of isopropenylacetate, and 0.5 g. of benzene sulfonic acid is then added. Afterstanding overnight at room temperature, most of the solvent is removedunder reduced pressure and methylene chloride added. The organic extractis washed with sodium carbonate solution, water, dried and evaporated.The residue is crystallized from hexane-ether to yieldpregnan-3a,1lfl,l7a,20ptetrol tetra-acetate.

EXAMPLE XI Pregmm-I1B,2I-di0l-3,20-dione diacetate Two grams ofpregnan-l1 3,2l-diol-3,20-dione were dissolved in ml. of chloroformcontaining 1 g. of benzene sulfonic acid. Ketene is then bubbled in foran hour at room temperature after which the organic layer iswashed withsodium carbonate solution, water dried, and evaporated. Crystallizationof residue from aqueous methanol yields pregnan-ll13,2l-diol-3,20-dionediacetate EXAMPLE XII M-pregrren-l1 8,21-di0l-3,20-dione II-acetate vHydrolysis of the 11,3,21-diacetate of Example XI with e a t lka am .p-1. 5.21a s aza 1 te m t o ace l a 'e b d h r hroniination in the usualmanner, gives .A -preg'nen-. 1'1p 21-.diol-3,20-dione ll-acetate(corticosterone 'l'l-acetate).

EXAMPLE. .xm

EXAMPLE Allo-pregnan-l 15170 20521 tetrol-3-0ne tetra-acetate Two gramsof allopregnamllp,17a;20p,21 tetrol-3-one are dissolved 'indtl of aceticanhydride and 105ml. of acetic acid. fOne gram of trichloraceticacidisthen added and the .acetylation allowed to proceed at room temperature.After work-,up in the usual manner, there isobtainedallo-pregnan-l15,17a,20 3,21-tetrol-3-one tetraacetate .crystallizablefrom ether.

EXAMPLE .Xv

A -etiochlene-1 I ii-013,1 7-"dione 1 1 -acetate One :gram of A-etioch0lene-1-113 0113,17-dionein .15 ml. of acetic anhydride and 15m1. of aceticacid is treated with '05 g. offbenzenesiilfonic acid.Following "the reaction at roomftemperature for the required period, theproduct is worked up as previously described, andthe r e is obtained Aetiocholene-l1'B-ol-3,lffidione 1 l-a'c'etate.

EXAMPLE XVI Androstan-3 '1 5;] 7 fi-triol triacetate Two grams of'androstan-Iid'llB,17B triol are reacted with acetic anhydride, aceticacid and p tolu'enesultonic acid at room temperature. Dilution "with wheand extraction with chloroform yields andros tan-3j8,'11]3jl7fl trioltriacetate. Partial hydrolysis as :above described, yieldsandrostan-3;8,l l ,3,l7,6-triol lI-acetate.

As above "indicated, the "acylation reaction is generally allowed .to'proceed :for a number of :hour's, preferably at room temperatures. Themaximum.acylation'temperature is below that at which dehydration orother:tin'desiredsi'de reaction sets in, and is generally-about :50 'C.

Using the procedures described in the above examples, the followingfurther llfi-ace'toxy steroids-can bereadily prepared:etiocholan-3a,11B,-l7fi triol .l'l-ace'tate and ;3,ll,l7-triacetate;etiocholan-3bc,l'l/3adio1-17-0ne .1 l-acetate and 3,11-diacetate;etiocholan-l 1/3-ol-3,17-dione 1.1- acetate; etiocholan-llfiglYfidiol-G-one ll-acetate and ll,17-diacetate; etiocholen -.llfil7l8ediolr3one ll-acetate and 11,17-diacetate; androstan-3a,llfl-diol-l7eone-1l--a'ce'tate and 3,1'l-di'acetate; androstan-11/3-0l-3,17- dioneil-acet'ate; andro'stanil lii-l7fi diols3 o ne ll-acetate and11,17-diacetat'e; pregnan,a;1'l33-diol-20-one '11-ace'- tate and =3; 1l-;d'iacetate; pregnan-1-l5 ol 3,2() dione 11 1- acetate;pregnan{3'u;1'1'j3,20a=triol l'l acetate and 3,11,20 t'ri'ace't'ate;pregnanfdaglrljfififlo-trio'l ll-acetate land 3,ll,20-triac'eta'te;pregnan-d rprzo'a-dibt-a-bne "rl-ac'tafe and 11,20-diacetate;,pregnan-gll15?;2013-diol-3-one ll-acetate and 1.},20-diacetat9; v;A;pregnen-.llfl-ol-EZ,QO-dione ll-aceta'te; 'A pre'grien-llfl,2'0a-diol-3-one ll-acetate and 11,2.0-diacet a te; ,A -pregnen-f 11p,20,B-dio.l-3-one l l-acetate and ILZO-diacetate;pre'gn'an-3'a,l1B,l7iz,20}8,21-penta-ol ll-acetate and penta-acetate; A-pr'egnen-llfi,l7u,21-triol- 3,20-dione 11,17-diacetate and11,17,21-triacetate; A pregnen-I1B,'17a,20 8,2'1 tetrol l l-acetate andtetra-acetate; pregnan-3a,l1fi,20fl,21-tetro1 ll-acetate andtetraacetate; .A -pregnen-l1p,20p,21-triol-3-one v1 l-acetate andtriacetate; pregnan-3a,1lB,l7a,20,B-tetrol ll-acetate and tetra-acetate;-pregnan-l1B,20B,2ltriol-3-one 11-acetate and triacetate; pregnan-llfi,l7u,20fl-triol-3-one ll-acetate and 'tr'iacetate; -'A-pregnen-11,8,l7a,20B-triol-3-one llacetate and triacetate;allopregnan-l15,205-diol-3-one 1'1- acetate and diacetate;allopregnan-3a,113,20,3-tri0l 11- 'acetate and tr'iacetate;allopregnan-3a,11p,17a,20B-tetrol ll-acetate and tetra-acetate;allopregnan-l1fl,17a,20}3- triol-3-one ll-acetate and triacetate;allopregnan- 30,l 1 3,20fi,21-tetrol ll-acetate and tetra-acetate;allopregnan-l118,205,21-triol-3-one 1 l-acetate and triacetate;l6u,l7u-oXidopregnan-3a,116,2l-tfiol-20-one 1 l-acetate and3,ll,2l-triacetate; l6bt,l7u-oxidopregnan-l15,21- didl -3,20-dione li-acetate and 11,21-diacetate; :,17w =oXido-A' -pregneh-l1;3,21diol-3,20-dione 'll-acet'ate and 11,21-diacetate; 16a,l7a-oxido-A-pregnen-1113-01-3 one l'l aeetate; and -l6a,17a-oxidopregnan-1l,8ol-3,20-dione ll-acetate.

'By strong acid 'as employed herein is-meant an-acid having adissociation constant K equal to at least '10? Thisincludes thehydro'halic acids, like hydrochloric acid, which are generally not assatisfactory as those named hereinabove. The acid employed should,however, not be one which will oxidize the llfi-hydroxyl. For bestresults, as already indicated, the acylation of the 11,8-hydroxyls'hould take place at approximately room tem- :perature.

Variationsifrom the :specific .procedures set out herein- ;a'bove may.be ."resorted to within the scopes of the .ap- .pended :claims withoutdeparting from the spirit of the invention. .Tihus, to prepare A-pregnen-11B,17a,2l-triol- -3,20-.dione;1'1,17,2 1-triacetate (or otherester), compound VIII orIXcan be further acylated in knownmanner;fwhileto produce the 11,17-diacetate, the triacetate can bepartiallyhydrolyzed at room or slightly elevated temperatures with sodiumcarbonate.

We'claim:

1. Process for .the manufacture of M-pregnen- .1'l78,'l'lu,2ltrio1-3,20%dione ll-acetate, which comprises reactingpregnan-3a,l1fl,l7a-triol-20;one with an acetylating agent at roomtemperature in the presence of a strong acid, partially hydrolyzing theresulting triacetate to .the .l1/3-acetoxy 3a,l7a-di0l, introducingbromine into .the Zl-pOsition, replacing the 2l-bromo group with amember of the class consisting of acyloxy and hydroxyl groups,theiacyloxy group being that of a lower aliphatic carboxylic acid,oxidizing the 3-secondary'hydroxyl to a keto group, class consisting ofacyloxy and hydroxyl groups, oxidizing the 3-secondary hydroxyl to aketo group, introducing bromine into the 4-position of the 3,20-di0neand dehydrobrominating and hydrolyz ing the 2l-acyloxy group whenpresent.

2. Process for the manufacture of A -pregnen-11fl,l7adiol-3,20-dionell-acetate which comprises reacting pregnan-3a,l1/3-l7a-triol-20-onewith an acetylating agent at room temperature in the presence of astrong acid, partially hydrolyzing the triacetate to the llB-acetoxy-'3a,l7a-dio1, oxidizingthe 3-secondary hydroxyl group to a keto'group,'introducing bromine into the 4-position and dehydroa'brominatingthe resulting 4-bromo-pregnan- 'ltlfl,'l7a-diol-3,20 dione ll-acetat'e.

3. Process for the manufacture of'an l ljfl-acetoxy-20- ketosteroidofthenormal'and allo-pregnane series having noother "substituentin the(B ring, which 'compn'ses reacting an l lfi hydroxy-idketo steroid ofthe normal and allo-pre'gnane series having no othersubstitu'ents in'the- C-r'ing with an'ace'tylatingagent "at room "temperature and in thepresence of a nee strong acid.

allo-pregnanes of the formula:

0mm (B0 L- and pregnenes of the formula CHlRI $0 LFR:

10 wherein R0 is a lower alkanoyloxy group, and R2 is a member of theclass consisting of H, OH, and lower alkanoyloxy and benzoyloxy groups.

5. A -pregnen-I1B,17a,21-triol-3,20-dione ll-acetate. 5 6. A-pregnen-11p,17a,21-trio1-3,20-dione 11,17-diacetate.

7, A -pregnen-11p,17a,21-t1io1-3,20-dione 11,21-diacetate.

8. A -pregnen-l1B,17a,21-t1i01-3,20dione 11,17,21-t1'i- 10 acetate.

Reichstein: Helv. Chim. Acta 19, 37-38 (1936). Fieser et al.: NaturalProducts Related to Phenam 20 threne, 3rd ed., pp. 407, 425-26 (1949).

4. A COMPOUND OF THE GROUP CONSISTING OF NORMAL AND ALLO-PREGNANES OFTHE FORMULA: